European Journal of Clinical Pharmacology

Tomson, Y.; Wessling, A.; Tomson, G.

doi: 10.1007/BF02570500pmid: 7867673

228 47 47 3 3 Y. Tomson A. Wessling G. Tomson Department of Clinical Neuroscience and Family Medicine, Section of Family Medicine Karolinska Institutet Diagnosvägen 8 NB S-141 54 Huddinge Sweden National Corporation of Swedish Pharmacies Stockholm Sweden Department of Clinical Pharmacology, Karolinska Institutet Huddinge Hospital Huddinge Sweden Department of International Health and Social Medicine Unit of International Health Care Research (IHCAR), Karolinska Institutet Stockholm Sweden Abstract In the south west region of Stockholm a group of 125 general practitioners (GPs) at 27 health centres asked about the extent to which the drug formulary of the University Hospital was useful in their practices. To answer this question, the GPs asked their local pharmacies for prescribing data. When presented this started a process towards rational prescribing from within the group of GPs, including repeated prescribing surveys, starting with health centres as the unit of analysis and proceeding to individual prescribing analyses on request by the GPs. As the prescribing data revealed major differences between health centres, the GPs arranged two workshops on drug use in primary health care. They developed a list of 167 recommended drugs based on drug statistics and morbidity in general practice. Signs of increased cost cautiousness could be shown. There was a clear trend towards both smaller volumes and cost per prescription item for the health centres in the study area. Compared to the national prescribing pattern, prescribing practice in the study area represented a 20 per cent lower drug cost. Although the GPs decided on a drug list separate from that of the hospital, collaboration between the Drug and Therapeutic Committee at the hospital and the GPs increased as a result of their increased engagement in drug management, thereby also bridging the gap between primary health care and clinical pharmacology.

Brøsen, K.; Gram, L.; Nielsen, P.; Brusgaard, K.; Skjødt, K.

doi: 10.1007/BF02570501pmid: 7867674

228 47 47 3 3 K. Brøsen L. F. Gram P. N. Nielsen K. Brusgaard K. Skjødt Department of Clinical Pharmacology Odense University Winsløwparken 19 DK-5000 Odense Denmark Department of Medical Microbiology, Institute of Medical Biology Odense University Winsløwparken 19 DK-5000 Odense Denmark Abstract CYP2D6 genotyping was carried out by XbaI restriction fragment length polymorphism analysis and polymerase chain reaction in 168 healthy Danish volunteers, 77 extensive metabolizers (EM) and 91 poor metabolizers (PM) of sparteine. All EM were genotyped correctly as heterozygous or homozygous for the functional (wild type) gene, D6-wt. However, the D6-wt gene was apparently also present in 11 (12%) of the PM who accordingly were incorrectly genotyped as EM. The specificity of genotyping PM thus was 100% but the sensitivity was only 88%. The most common allele was the D6-wt with an apparent frequency of 0.741 (0.026) in the Danish population and the second most common allele was the D6-B with an apparent frequency of 0.194 (0.024). The median (range) of the sparteine metabolic ratio (MR) in 47 homozygous D6-wt EM was 0.28 (0.11–4.10) and the corresponding value in heterozygous EM was 0.36 (0.11–9.10). The median difference was 0.09 (95% confidence interval: 0.02–0.16). CYP2D6 phenotyping is a promising tool in tailoring the individual dose of tricyclic antidepressants, some neuroleplics and some antiarrhythmics. However if the genotype test could be improved with regard to both sensitivity in PM and the ability to predict CYP2D6 activity in EM then it would be of even greater clinical value in therapeutic drug monitoring.

Wensing, G.; Heinig, R.; Priesnitz, M.; Kuhlmann, J.

doi: 10.1007/BF02570502pmid: 7867675

228 47 47 3 3 G. Wensing R. Heinig M. Priesnitz J. Kuhlmann Pharma, Research and Development Institute of Clinical Pharmacology International Bayer AG D-42096 Wuppertal Germany Abstract Leukotrienes (LT) have been proposed to play an important role in the pathogenesis of asthma. This paper reports the results of two studies investigating the effect of BAY x 7195, a new oral receptor antagonist of cysteinyl-leukotrienes, on LTD 4 -induced bronchoconstriction in healthy male volunteers. Using a double-blind, placebo-controlled, crossover design, volunteers received 250 mg ( n =6; study 1) and 100 and 500 mg ( n =6; study 2) of BAY x 7195. Bronchoprovocation with nebulized LTD 4 was performed 2 (250 mg) and 2 and 8 (100 and 500 mg) hp.a. The specific airway's conductance (SGaw) was used to assess the airway's response. Blood samples to determine plasma concentrations of BAY x 7195 were taken at the end of bronchoprovocation. BAY x 7195 showed no effect on baseline lung function. Compared to placebo, the different doses of BAY x 7195 increased the concentration of LTD 4 needed to produce a 35% decrease in SGaw 2h p.a. between 1- and 23-fold. Eight hours p.a., 100 and 500 mg caused shifts in the concentration-response curve of between 1- and 13-fold. There was no predictive relationship between plasma concentrations of BAY x 7195 and the response to LTD 4 challenge. However, there was a relationship between dose and effect. No relevant adverse effects were reported. In conclusion, the present results suggest that BAY x 7195 is an effective LTD 4 -receptor antagonist in man.

Müller, P.; Cohen, T.; Gasparo, M.; Sioufi, A.; Bacine-Poon, A.; Howald, H.

doi: 10.1007/BF02570503pmid: 7867676

228 47 47 3 3 P. Müller T. Cohen M. de Gasparo A. Sioufi A. Bacine-Poon H. Howald Research and Development Departments Pharma Division, Ciba-Geigy Limited CH-4002 Basel Switzerland Abstract Valsartan (CGP 48933), a specific blocker of the angiotensin II (Ang II) receptor subtype 1 (AT 1 receptor) was administered in single, oral doses of 40 mg and 80 mg to six healthy, normotensive male volunteers in a double-blind, placebo-controlled, randomized crossover trial. The aims of the study were a) to assess the extent, time course and dose-dependency of inhibition of the pressor effect of exogenous Ang II; and b) to attempt to correlate AT 1 receptor blockade with the drug levels in plasma and with other markers of biological activity of the trial drug such as plasma renin activity (PRA). Using the Finapres device and i.v. bolus injections of exogenous Ang II, AT 1 receptor blockade was assessed by measuring blood pressure (BP) and heart rate (HR) on a beat-by-beat basis. A dose-response curve for Ang II was obtained for each subject before and at 2,4, 6,8 and 24h after administration of placebo and of the two doses of valsartan. PRA was measured with a conventional radioimmunoassay method. Data evaluation included a) descriptive analysis of the changes of the Ang II dose-response curves after valsartan, as compared to the curve on placebo; b) calculation of the pressor dose D 30 of Ang II at each timepoint, using linear regression; c) assessment of the effect of 4 μg Ang II on systolic BP and HR and the calculation of the percentage inhibition of these effects after valsartan; d) description of the relationship between drug levels in plasma and the measures of AT 1 blockade, including pharmacokinetic-pharmacodynamic modeling with an E max model for the percentage inhibition of systolic BP and HR. It is concluded that (a) the methodology used is suitable to evaluate AT 1 receptor blockade in man; (b) instead of using a full dose-response curve for Ang II at each timepoint, an abbreviated approach with only one pre-determined Ang II dose may be adopted without substantial loss of information; (c) valsartan is an inhibitor of the AT 1 receptor in man, with a mean E max of 74% and a mean IC 50 of 0.53 μmol·1 −1 for the blood pressure response to exogenous Ang II; (d) receptor blockade after single oral doses of 40 mg and 80 mg valsartan reaches its maximum at 2 h and is detectable up to 24 h after administration; (e) despite a doubling of systemic exposure, the relationship between dose and receptor blockade appears to be rather flat in the dose range 40 to 80 mg; and (f) valsartan is well tolerated by healthy subjects in the dose range tested.

Legnani, C.; Palareti, G.; Biagi, R.; Ludovici, S.; Coccheri, S.; Maggiore, L.; Milani, M.

doi: 10.1007/BF02570504pmid: 7867677

228 47 47 3 3 C. Legnani G. Palareti R. Biagi S. Ludovici S. Coccheri L. Maggiore M. R. Milani Department of Angiology and Blood Coagulation University Hospital S. Orsola Via Massarenti, 9 I-40138 Bologna Italy Opocrin S.p.A. Corlo Modena Italy Alfa Wassermann Group Bologna Italy Abstract The acute and chronic effects on blood coagulation and fibrinolysis of a new molecular weight dermatan sulphate (Desmin 370) have been investigated in a double blind, placebo-controlled cross over study in 12 healthy volunteers. The compound (100 and 200 mg) was injected IM and the expected heparin cofactor II potentiating effect, reflecting dermatan sulphate activity, peaked after 2h and was still detectable after 9 h. Surprisingly for this type of compound, a substantial increase in anti-Xa activity also appeared and lasted up to 12 h in the absence of a significant change in aPTT. The bovine-thrombin time was not changed, while human-thrombin times were slightly, albeit non-significantly, prolonged. The activity of t-PA was increased 6h after the higher dose, but the overall pattern of fibrinolytic activities did not suggest any important change after drug treatment in comparison to placebo. No residual or cumulative effect on any of the investigated parameters was detectable 24h after the injection on the 4th and 8th days during repeated daily administration. Parallel in vitro and in vivo investigations showed that the unexpected anti-Xa effect was not attributable to contamination by traces of low molecular weight heparin. Desmin 370, a low molecular weight dermatan sulphate that potentiates heparin cofactor II and also inhibits Factor Xa, deserves clinical evaluation as an antithrombotic agent.

Vuurman, E.; Uiterwijk, M.; O'Hanlon, J.; Rosenzweig, P.

doi: 10.1007/BF02570505pmid: 7867678

228 47 47 3 3 E. F. P. M. Vuurman M. M. C. Uiterwijk J. F. O'Hanlon P. Rosenzweig Institute for Human Psychopharmacology Abstraat 2 a 6211 LS Maastricht The Netherlands Synthélabo Recherche (L.E.R.S) Bagneux France Abstract The acute effect of doses of mizolastine 5, 10, 20 and 40 mg, an active control (clemastine 2 mg) and placebo on actual car driving and psychomotor performance have been compared. Twenty four healthy volunteers were treated according to a double-blind, 6-way cross-over design. In the driving test, lasting about 1 h, lateral position control and speed were continuously measured; the psychomotor test battery, lasting 50 min, comprised critical flicker-fusion frequency, critical instability tracking, divided attention, memory search and choice reaction time, and vigilance studies; and mood changes and possible adverse-effects were rated on visual analogue scales. The results showed a dose-response relationship: mizolastine 40 and 20 mg impaired driving and psychomotor performance. The effect of mizolastine 40 mg on driving was strongly correlated with that of clemastine ( r =0.78) and was comparable to the effect of a blood ethanol level of 0.8 mg·ml −1 . Mizolastine 5 mg and 10 mg did not have a significant effect on driving performance and psychomotor tests. It was concluded that at a 10 mg dose of mizolastine, the therapeutic dose, it could be considered a safe antihistamine, although individual adverse reactions cannot be completely ruled out.

Ramaekers, J.; O'Hanlon, J.

doi: 10.1007/BF02570506pmid: 7867679

228 47 47 3 3 J. G. Ramaekers J. F. O'Hanlon Institute for Human Psychopharmacology University of Limburg Abtstraat 2A 6211 LS Maastricht The Netherlands Abstract The study was conducted according to a nineway, observer- and subject-blind, cross-over design. Its purpose was to compare the single-dose effects of the following drugs on driving performance: acrivastine (8, 16 and 24 mg); the combination of acrivastine (8 mg) with pseudoephedrine (60 mg); terfenadine (60, 120 and 180 mg); diphenhydramine-HCL (50 mg); and placebo. The subjects were 18 healthy female volunteers. Drug effects were assessed in two repetitions of two driving tests (highway driving and car-following) after each treatment. Acrivastine's impairing effects in both driving tests were similarly dose-related. The 8-mg dose had a small, but significant, effect on highway driving in the first trial. The 16-mg and 24-mg doses significantly impaired driving in both tests during the first trial and the 24-mg dose did so again during the second trial. Neither the combination of acrivastine with pseudoephedrine nor terfenadine caused any significant impairment of performance. Diphenhydramine significantly impaired driving in both tests during every trial. In conclusion, the normal therapeutic dose of acrivastine (8 mg) had little effect on driving performance, and virtually none when that dose was given in combination with pseudoephedrine (60 mg). Higher doses of acrivastine severely impaired driving performance. Terfenadine had no significant effect on driving performance after any dose while diphenhydramine strongly impaired every important driving parameter.

Lilleberg, J.; Nieminen, M.; Sundberg, S.; Häyhä, M.; Akkila, J.

doi: 10.1007/BF02570507pmid: 7867680

228 47 47 3 3 J. Lilleberg M. S. Nieminen S. Sundberg M. Häyhä J. Akkila Cardiovascular Laboratory, First Department of Medicine Helsinki University Central Hospital FIN-00290 Helsinki Finland Orion-Farmos Pharmaceuticals Espoo Finland Abstract Levosimendan is a new calcium-sensitiser intended for the treatment of congestive heart failure. The results of preclinical studies indicate it has positive inotropic and vasodilator effects. In the open study reported here up to 5 mg levosimendan and vehicle were administered to 8 healthy male volunteers at one- to 2-week intervals. Efficacy was evaluated using M-mode echocardiography, and by measuring systolic time intervals, recording ECG and measuring blood pressure. For almost all haemodynamic parameters except heart rate (HR) the maximum effect was seen 10 or 20 min after drug infusion. Effects 10 min after infusion of drug and vehicle were compared. HR was significantly increased 10 min only after infusion of 5 mg: significant increases were seen 60 min after infusions of 2, 3 and 5 mg (4, 8 and 17 beats min −1 , respectively). Diastolic blood pressure was significantly lower after doses of 1 mg or more. The decrease after 5 mg was 17 mm Hg. Systolic blood pressure tended to increase. Fractional shortening (FS) and ejection fraction (EF) increased significantly after doses of 1 mg and higher. EF 10 min after infusion of vehicle was 54%. It increased to 73% after 5 mg. Decreases in electromechanical systole (QS2 i ) 10 min after 2, 3 and 5 mg were significant. There were no clinically significant adverse events or changes in laboratory safety values. The changes in QS2i, FS, EF and blood pressure indicate that levosimendan has positive inotropic and vasodilator effects in healthy subjects.

Gatti, G.; Bartoli, A.; Perucca, E.; Bertin, D.; Strolin-Benedetti, M.

doi: 10.1007/BF02570508pmid: 7867681

228 47 47 3 3 G. Gatti A. Bartoli E. Perucca D. Bertin M. Strolin-Benedetti Clinical Pharmacology Unit, Institute of Medical Pharmacology University of Pavia, Piazza Botta 10 I-27 100 Pavia Italy Pharmacia-Farmitalia Carlo Erba Milan Italy Alcon Italia Centro Direzionale Lombardo, Cassina De'Pecchi Milan Italy Abstract The pharmacokinetics and pharmacodynamics of rolafagrel (FCE 22178), a novel thromboxane synthase inhibitor, were evaluated after single and multiple oral doses in eight healthy volunteers. After a single dose (400 mg), the drug was absorbed rapidly, peak plasma concentrations being attained within 2 h in all subjects. Elimination followed a biphasic course, with a rapid initial decline followed after 12–24 h by a late phase with a terminal half-life of about 10h. About 100% of the administered dose could be recovered in urine within 72 h, mostly in conjugated form. During multiple dosing (400 mg t.i.d. for 5 days), steady-state conditions were approached on day 2 and AUC values over a dosing interval were similar to those observed after a single dose (72.3 vs 76.3 μg·ml −1 ·h). Pharmacokinetic parameters calculated after multiple doses were similar to those observed after a single dose (C max : 20.1 vs 18.2 μg·ml −1 ; t max : 1.2 vs 1.1 h; terminal half-life: 10.9 vs 11.4 h; CL: 85.2 vs 70.4 ml·h −1 ;V: 1.23 vs 1.241·kg −1 ). Platelet generation of thromboxane B 2 , the stable breakdown product of thromboxane A 2 , was inhibited by 85% at a plasma rolafagrel concentration of about 4μg·ml −1 , and only a small increase in inhibition was observed at higher concentrations.

Lijnen, P.; Petrov, V.; Amery, A.

doi: 10.1007/BF02570509pmid: 7867682

228 47 47 3 3 P. Lijnen V. Petrov A. Amery Hypertension Unit B-3000 Campus Gasthuisberg, Herestraat 49 Leuven Belgium Abstract In vitro incubation of human erythrocytes and platelets with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin in the concentration range 1 nM to 10μM did not affect the activity of the Na + −K + -pump, Na + −K + -cotransport or Na + −Li + -countertransport, or the ground membrane leak for Na + and K + . The data indicate that pravastatin has no direct effect on transmembrane cationic transport systems in red blood cells or platelets.